氨基糖在二糖蒽环类药物DNA结合中的作用：复合物MAR70/d(CGATCG)的晶体结构

Role of the amino sugar in the DNA binding of disaccharide anthracyclines: crystal structure of the complex MAR70/d(CGATCG).

作者信息

Temperini Claudia, Cirilli Maurizio, Aschi Massimiliano, Ughetto Giovanni

机构信息

Department of Chemistry, University of Florence, 50019 Sesto F.no (FI), Italy.

出版信息

Bioorg Med Chem. 2005 Mar 1;13(5):1673-9. doi: 10.1016/j.bmc.2004.12.007.

DOI:10.1016/j.bmc.2004.12.007

PMID:15698785

Abstract

Disaccharide anthracyclines analogues have been shown to exhibit different antitumour activity as compared with parents compounds doxorubicin and daunomycin. Here we report the crystal structure of the disaccharide analog MAR70 complexed with the DNA hexamer d(CGATCG). The structure has been solved at 1.54A resolution and is similar to previous crystallized anthracycline-DNA complexes with both sugar rings of the disaccharide chain lying in the DNA minor groove. Comparison with the structure of MEN10755 another disaccharide anthracycline co-crystallized with the same DNA hexamer suggests a correlation between the position of the amino sugar on the disaccharide chain and the conformation of this moiety when binding to DNA. This is discussed with respect to the influence on drug activity and on the possible interaction with other cellular targets.

摘要

与母体化合物阿霉素和柔红霉素相比，二糖蒽环类类似物已显示出不同的抗肿瘤活性。在此，我们报告了与DNA六聚体d(CGATCG)复合的二糖类似物MAR70的晶体结构。该结构已在1.54埃分辨率下解析，并且与先前结晶的蒽环类-DNA复合物相似，二糖链的两个糖环都位于DNA小沟中。与另一种与相同DNA六聚体共结晶的二糖蒽环类化合物MEN10755的结构比较表明，二糖链上氨基糖的位置与该部分与DNA结合时的构象之间存在相关性。本文就其对药物活性的影响以及与其他细胞靶点可能的相互作用进行了讨论。